SYNOPSIS Blastomycosis in Minnesota, USA, 1999–2018 · Risk factors for sporadic cases are less...

Blastomycosis in Minnesota, USA, 1999–2018

Malia Ireland, Carrie Klumb, Kirk Smith, Joni Scheftel

866 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 26, No. 5, May 2020

Author affiliation: Minnesota Department of Health, St. Paul, Minnesota, USA

DOI: https://doi.org/10.3201/eid2605.191074

Blastomycosis is a systemic disease caused by Blas-tomyces spp. fungi. To determine its epidemiology in blastomycosis-endemic Minnesota, USA, we evalu-ated all cases reported to public health officials during 1999–2018. We focused on time to diagnosis, expo-sure activities, and exposure location. A total of 671 cases and a median of 34 cases/year were reported. Median time to diagnosis was 31 days; 61% of patients were not tested for blastomycosis until they were hos-pitalized. The case-fatality rate was 10%, and patients

SYNOPSIS

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Release date: April 16, 2020; Expiration date: April 16, 2021 Learning Objectives Upon completion of this activity, participants will be able to:

• Assess the epidemiology of blastomycosis in the current study • Evaluate clinical characteristics of patients with blastomycosis • Describe diagnostic delay among patients with blastomycosis • Analyze exposure histories among patients with blastomycosis

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Authors

Disclosures: Malia Ireland, DVM; Carrie Klumb, MPH; Kirk Smith, DVM, PhD, MS; and Joni M. Scheftel, DVM, MPH, have disclosed no relevant financial relationships.

who died were 5.3 times more likely to have a concur-rent medical condition. Outdoor activities and soil ex-posure were reported by many patients, but no specific activity or exposure was common to most. Almost one third of patients were probably exposed in geographic areas other than their home county. Providers should consider alternative etiologies for patients with pneu-monia not responding to antibacterial treatment, and public health officials should increase awareness in blastomycosis-endemic areas.


Blastomycosis is a systemic disease caused by thermally dimorphic Blastomyces spp. fungi

found in soil. Infection with B. dermatitidis or B. gilchristii occurs primarily by inhalation of conidia and most often causes pneumonia, although direct inoculation of soft tissue can occur (1). Infections can disseminate hematogenously, most commonly to skin, bone, and the central nervous system (2). Case-fatality rates range from 6% to 22% (3–5). Most patients are male (60%–75%) (3–8) and middle-aged (median age 41–44 years) (3,5,7,8). Diagnosis is of-ten delayed because community-acquired bacterial pneumonia has a similar presentation (9,10) and index of suspicion for blastomycosis is low among healthcare providers (1,11). The standard diagnos-tic method is isolation and identification of Blasto-myces spp. in culture from clinical specimens, but also used are histopathology, cytopathology, anti-gen testing, and antibody testing (1).

In North America, blastomycosis occurs primar-ily in areas surrounding the Great Lakes, the Missis-sippi and Ohio River valleys, and the St. Lawrence River, which include many US states and Canada provinces (1,2). Recent phylogenetic studies and ecologic niche modeling reports have increased our knowledge of the distribution and ecology of Blasto-myces spp. (12–15). However, the difficulty of isolat-ing the organism directly from environmental sam-ples limits our ability to determine its true endemic ranges (12). Case series and outbreak reports have provided insight into the ecology of Blastomyces spp. and possible risk factors for human infection (16–19). Outbreaks have been associated with outdoor recre-ation (17,20–22) and with construction, excavation, or local environmental sources such as yard waste com-post (18). Incidence or mortality rates are increased among black (3,4,23), Asian (24), American Indian/Alaska Native (23), and Aboriginal Canadian persons (5). Risk factors for sporadic cases are less well docu-mented; a retrospective case–control study did not find associations with classic outbreak exposures (4).

To better describe the epidemiology of blastomy-cosis in Minnesota, an endemic area, we evaluated all cases reported to public health officials during 1999–2018. We also examined delayed recognition and di-agnosis of the disease.

MethodsBlastomycosis has been reportable to the Minneso-ta Department of Health (MDH) since 1985. Begin-ning in 1999, MDH routinely collected information on demographics, illness history, diagnostic test results, treatment, outcomes, and any exposures

by using a standardized case report form. Data col-lection evolved over time; during 1999–2015, case report forms were completed by providers or their staff, and during 2016–2018, MDH staff abstracted medical records and completed case report forms. During the entire study period, a confirmed case of blastomycosis was defined as illness in a Minne-sota resident with any of the following: a positive Blastomyces culture, Blastomyces organisms visual-ized in tissue or body fluid, or a positive Blasto-myces antigen test result and compatible clinical illness (e.g., cough, fever, abnormal pulmonary imaging, or skin lesions). Cases were classified as pulmonary only, nonpulmonary (localized disease outside the pulmonary system with no clinical pul-monary illness), or disseminated (disease in both the pulmonary system and at least 1 other system/site). We collected illness onset date, date of first visit to a healthcare provider, and date of the first test for blastomycosis regardless of test result. To assess diagnostic delays, we defined the patient interval as the time between illness onset and first visit to healthcare and the provider interval as the time between first healthcare visit and sample col-lection date for the first blastomycosis test (which indicates that a blastomycosis diagnosis was under consideration). Total time to diagnosis was defined as the time from illness onset to the first test for blastomycosis. We used the date of first test regard-less of result to evaluate the time until healthcare providers considered a systemic mycotic infection. Doing so eliminated the variability in growth rate of Blastomyces cultures.

We attempted to interview all patients or next of kin regarding patients’ illness and exposure history during the 3 months before illness onset, including home and neighborhood environment, occupation, outdoor activities and travel, concurrent medical conditions, immunosuppressive medications, smok-ing history, and family members or pets with a blastomycosis diagnosis. Underlying conditions in-cluded diabetes mellitus, chronic lung disease (e.g., chronic obstructive pulmonary disease, asthma), chronic liver disease (e.g., cirrhosis, hepatitis), and other chronic illnesses (e.g., HIV infection/AIDS, sarcoidosis, heart disease, kidney disease). Immuno-suppressive medications included corticosteroids, tumor necrosis factor–α blockers, chemotherapy, or posttransplant medications. Patients were also asked about any information missing from case re-port forms regarding demographics, symptoms, and prescribed antibacterial and antifungal drugs. On the basis of exposure information obtained during

Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 26, No. 5, May 2020 867

SYNOPSIS

interviews, we assigned the most likely location of Blastomyces exposure for each patient, either a specif-ic Minnesota county or an out-of-state location. This subjective assessment considered incubation period, travel, and activities.

We included in our analysis confirmed cases with a positive specimen collection date of 1999 through 2018. We did not include patients with pos-itive antigen test results but no compatible illness, positive serologic antibody tests only, or other fun-gal infections.

We calculated incidence by race by using the number of cases and race population in Minnesota for each year (25) and then averaged the yearly in-cidence rates. We calculated incidence by county by using the average population of each county for the entire period and the average number of cases in each county. We classified counties with an incidence rate of >3 cases/100,000 population as highly blastomyco-sis-endemic counties, based on a natural break in the distribution of incidence by county.

We analyzed data by using SAS 9.2 statistical software (https://www.sas.com) and conducted univariate analysis by using χ2, Fisher exact, Student t, Wilcoxon rank-sum, and Kruskal-Wallis tests. To control for race and sex in analyses of outcome and concurrent conditions, we used multivariate logistic regression. We considered 2-sided p-values of <0.05 to be significant.

Results

DemographicsDuring the 20-year study period, 671 confirmed cases of blastomycosis were reported in Minnesota;

the median number of cases per year was 34 (range 22–58) (Figure 1). A total of 32 (5%) cases were part of outbreaks with patient exposure in Minnesota or Wisconsin, including a large 1999 outbreak in St. Louis County, Minnesota, which involved humans and dogs and was associated with wet weather and an excavation site for a new neighborhood. Except for 1999, more cases were reported during 2016–2018 than during previous years.

The statewide average annual incidence was 0.64 cases/100,000 population. Average annual inci-dence ranged from 0 to 7.6 cases/100,000 for individ-ual counties (Figure 2). The median patient age was 44 years (range 3–93 years), and 474 (71%) patients were male (Table 1; Figure 3). The average annual incidence was highest for American Indian/Alaska Natives (2.7/100,000 population), followed by white (0.53/100,000), Asian/Pacific Islander (0.51/100,000), and black (0.48/100,000) persons.

Clinical CharacteristicsReported symptoms included cough (83%), fatigue (79%), fever (69%), weight loss (62%), night sweats (61%), poor appetite (57%), chills (57%), joint pain (30%), back pain (28%), and skin lesions (25%). A total of 456/663 (69%) patients were hospitalized for a median of 8 (range 1–197) days (hospitaliza-tion data were not available for 8 patients). Most (72%) infections involved only the pulmonary sys-tem, 21% of infections were disseminated, and 7% were nonpulmonary localized infections (Table 1). The most common site was skin or soft tissue for disseminated infections (108 cases, 79%) and non-pulmonary infections (38 cases, 83%), followed by bones or joints (22 [16%] disseminated cases, 6


Figure 1. Blastomycosis cases per year, Minnesota, USA, 1999 –2018. No deaths occurred in patients with outbreak cases.


[13%] nonpulmonary cases) and the central nervous system (13 [9%] disseminated cases, 2 [4%] nonpul-monary cases). For 47% of patients, >3 courses of antibacterial drugs were prescribed before blasto-mycosis was diagnosed.

Diagnostic MethodsThe most commonly reported diagnostic test used was culture; 557/617 (90%) positive results were reported. Positive cytopathology results were re-ported for 250/539 (46%) patients and positive his-topathology results for 83/467 (18%). Samples ob-tained by bronchoalveolar lavage or tracheal swab were the most common sources for culture (269/567 [47%] patients) and cytopathology (123/273 [45%] patients). Antigen testing became available in 2003 but was not widely used until 2008. Of the 401 pa-tients from 2008–2018, a positive urine or serum an-tigen test was included in the diagnostic testing for 167 (42%). Use of antigen tests to evaluate treatment efficacy was not tracked.

Time to DiagnosisAmong all patients, the median total time to diagno-sis was 31 (range 0–1,130) days, interquartile range [IQR] 16–64 days) (Figure 4). The median patient interval (time from illness onset to first visit) was 5 (range 0–409, IQR 0–15) days. The median provider interval (time from first visit to first blastomycosis test) was 14 (range 0–517, IQR, 6–32) days (Figure 4). Provider interval was >30 days for 27% of patients. The median total time to diagnosis for patients with nonpulmonary disease was 67 (IQR 39–150) days. For 61% of patients, blastomycosis testing was not performed until they were admitted to the hospital. The median time to diagnosis was 40.5 (IQR 22–58) days for Asian/Pacific Islander patients and 34 (IQR 12–60) days for American Indian/Alaska Native patients compared with 31 (IQR 16–66) days for white patients. However, these differences were not statisti-cally significant.

The overall time to diagnosis was the same in both highly blastomycosis-endemic and less blasto-mycosis-endemic counties. Hospitalization was more likely for patients living in less blastomycosis-endem-ic counties (72%) than for patients living in highly blastomycosis-endemic counties (64%) (odds ratio [OR] 1.4, 95% CI 1.02–1.99; p = 0.036).

TreatmentMedications used for blastomycosis treatment were not reported for all case-patients. Among those for whom they were reported, 462 (84%) case-patients received

itraconazole, 145 (26%) amphotericin B, 37 (7%) vori-conazole, and 28 (5%) other or unknown medications.

OutcomesThe overall case-fatality rate was 10% (yearly range 3%–16%). Although fatality rates were higher among persons in some racial groups (18% for American In-dian/Alaska Natives, 17% for Asian/Pacific Island-ers), no statistically significant differences were ob-served. Patients who died were significantly older than patients who survived; mean difference was 15 years (Table 1). No patients with nonpulmonary in-fections died. Among patients who did die, the me-dian time to diagnosis was significantly shorter than for those who survived (Figure 4).

Concurrent ConditionsConcurrent medical conditions or an immunocom-promised status resulting from illness or medication were reported by 195 (35%) patients (Table 1). Patients who were hospitalized were twice as likely as those not hospitalized to have a concurrent condition (OR 2.12, 95% CI 1.4–3.2; p<0.001). Patients who died were 5.3 times more likely to have a concurrent condition than were patients who survived (Table 1). The most common concurrent condition was diabetes. Current smoking was reported by 109 (20%) patients, and any history of smoking was reported by 194 (39%).


Figure 2. Average annual incidence of blastomycosis by county, Minnesota, USA, 1999–2018.

SYNOPSIS

ExposuresInterviews were conducted with 541 (81%) of 671 pa-tients or their next of kin (Table 2). In the 3 months before illness onset, 317 (59%) of 539 patients partici-pated in >1 outdoor activity including hunting, fish-ing, swimming, boating, camping, hiking, or biking. Of these, the most commonly reported were boating (40%), fishing (30%), and hiking (28%). At least 1 spe-cific soil exposure was reported by 375 (78%) of 480 patients; soil exposures included gardening, clearing or cutting wood, gathering wild plants, using an all-terrain vehicle (ATV), or being near excavation. Occu-pational exposure to soil, wooded, or boggy areas was reported by 97 (21%) of 468 patients. None of these ac-tivities or other exposures were reported by 31 (6%) pa-tients. Owning a dog was reported by 283 (53%) of 539 patients; of those, 29 (10%) reported owning a dog that had ever had blastomycosis. Having a family member who had ever had blastomycosis was reported by 22 (4%) of the 541 patients. A significantly higher propor-tion of male than female patients reported hunting, fishing, and using an ATV (Table 2), but we found no significant differences by sex for hiking, camping, gar-dening, nearby excavation, beaver dam exposure, or owning a dog. We also found no significant differences in exposures by sex among children <16 years of age.

Patients with prior medical conditions were less likely (47%) than previously healthy patients (64%) to report participation in outdoor activities (OR 0.49, 95% CI 0.33–0.71; p<0.001). The individual activities of fishing, camping, hiking, and swimming were re-ported significantly less often by patients with con-current conditions (data not shown).

A total of 340 (51%) of 671 patients were most likely exposed to Blastomyces in their county of resi-dence; 195 (29%) were exposed outside their county of residence, either in other Minnesota counties or other states (Figure 5). These locations included the highly blastomycosis-endemic northern Minneso-ta counties of St. Louis (27 patients), Cass (24), and Itasca (10); Wisconsin (52); and Canada (10). The most probable location of exposure was unknown for 136 patients (20%) because of multiple possible locations (21 patients [3%]) or because no interview could be conducted (115 patients [17%]).

DiscussionThe epidemiology and clinical courses of blastomy-cosis cases in Minnesota are similar to those in other disease-endemic regions. The case-fatality rate, sex ratio, age distribution, and reported symptoms are consistent with those reported from other disease-


Table 1. Blastomycosis patient demographics and health-related data, by outcome, Minnesota, USA, 1999–2018*

Category All patients,

n = 671 Patients with nonfatal

cases, n = 602 Patients with fatal

cases, n = 64 OR (95% CI)† p value† Mean age SD, y 44 19.2 42 18.5 57 20.7

p<0.001‡

Sex

NS M 474 (71) 426 (71) 45 (70)

F 197 (29) 176 (29) 19 (30)

Race

NS

White 490 (83) 446 (84) 44 (75)

American Indian/Alaska Native 40 (7) 32 (6) 7 (12)

Black 31 (5) 27 (5) 3 (5)

Asian/Pacific Islander 23 (4) 19 (4) 4 (7)

Other/Mixed race 4 (1) 4 (1) 0

Ethnicity

NS

Non-Hispanic 439 (96) 398 (96) 41 (95)

Hispanic 18 (4) 16 (4) 2 (5)

Location of disease

NS Pulmonary only 469 (72) 425 (72) 43 (69)

Disseminated 137 (21) 117 (20) 19 (31)

Nonpulmonary 46 (7) 46 (8) 0 Concurrent conditions

Any 195 (35) 157 (30) 36 (71) 5.3 (2.7–10.5) p<0.001 Chronic illnesses 109 (22) 87 (19) 20 (57) 5.5 (2.6–11.6) p<0.001 Diabetes mellitus 81 (17) 68 (16) 11 (42) 3.6 (1.5–8.7) p = 0.005 Chronic lung disease 15 (4) 11 (3) 4 (21) 10.2 (2.7–38.6) p<0.001 Immunocompromise 46 (11) 34 (8) 12 (44) 8.6 (3.4–21.8) p<0.001 Steroid use 15 (4) 8 (2) 7 (32) 21.1 (6.3–70.8) p<0.001 Rheumatoid arthritis treatment 13 (3) 9 (2) 4 (21) 10.6 (2.3–48.8) p = 0.002 Cancer 24 (6) 19 (5) 5 (25) 7.7 (2.4–25.5) p<0.001 *Values are no. (%) except as indicated. Denominators may not be same across categories because not all data were available for all patients. OR, odds ratio; NS, not significant. †ORs and p values calculated by using univariable logistic regression, except for concurrent conditions analyses, which were controlled for race and sex. ‡p value calculated by using Student t test.


endemic areas (3,5,7,8). Although case counts and fatality rates were higher in the most recent 2 years, we found no overall trends by year, race, or sex. The typical blastomycosis patient in Minnesota is a 45-year-old white man who spends time outdoors. However, this report highlights underrecognized features of blastomycosis epidemiology, particular-ly patients who do not fit the typical presentation or demographic.

Although the blastomycosis incidence rate was highest among American Indian/Alaska Natives, the incidence difference between that group and white, Asian, and black persons was not statistically significant. However, in Minnesota, the population of American Indian/Alaska Natives is much smaller than that of other races, which, combined with other factors such as prevalence rates for concurrent con-ditions or geographic location of residence, may influence incidence rates in the American Indian/Alaska Native population. For example, a larger proportion of American Indian/Alaska Native blas-tomycosis patients (70%) than patients of other races (38%) live in highly blastomycosis-endemic coun-ties (OR 3.9, 95% CI 1.9–7.8; p<0.001). Genetics may also play a role. Others have discussed increased susceptibility to disease or severe disease after Blas-tomyces infection for Asian, black, and American In-dian/Alaska Native persons (3,4,19,23,24,26). Our data show higher case-fatality rates for Asians and American Indians/Alaska Natives; however, the difference was not significant, even after controlling for sex and underlying conditions. Another study evaluating mortality rates found that the likelihood of dying from blastomycosis-related complications

was higher for American Indian/Alaska Native and black patients than for white patients (23). Variation in blastomycosis incidence and outcomes by race warrants further exploration (26).

Hospitalization and mortality rates were higher among patients with underlying conditions or immu-nocompromised status, as previously reported (5,7,27). Those patients reported outdoor and soil exposures less frequently than did previously healthy patients, which could lead a clinician to discount blastomycosis as a diagnostic possibility. Because the odds of death are dramatically higher for patients with an underly-ing condition than for previously healthy patients, ear-lier consideration of alternative pneumonia etiologies (beyond antimicrobial drug–resistant bacterial infec-tion) for those patients is warranted.

Diagnosis of blastomycosis is often delayed. For half of the patients in this study, >1 full month elapsed between illness onset and the patient’s first test that could diagnose blastomycosis. Diagnosis took even longer for those with nonpulmonary infections. Pro-vider interval accounted for a larger proportion of this time than did patient interval. Medical record abstraction provided ample anecdotal evidence that patients visited healthcare providers numerous times before their first blastomycosis test. These delays have many possible consequences, including unnec-essary antibacterial drug use and higher hospitaliza-tion rates. Being hospitalized seemed to be a key fac-tor in being tested for blastomycosis; 60% of patients were not tested until hospital admission. Earlier test-ing may have prevented some of these admissions. Relatively few patients underwent urine or serum antigen testing, which, despite cross-reactivity with


Figure 3. Age and sex distribution of 670 patients with blastomycosis, Minnesota, USA, 1999–2018.

SYNOPSIS

other fungal pathogens, may have provided guidance toward a general diagnosis of fungal disease and ap-propriate treatment.

Time to diagnosis should logically be shorter for patients with skin lesions because visible lesions might trigger sampling or consideration of blasto-mycosis in a patient with concurrent pneumonia. This result was found for 123 Mississippi patients, for whom clinicians correctly diagnosed 64% of blastomycosis cases for patients with skin lesions on their initial visit but only 18% of blastomycosis cases for all patients (28). However, in our study, we compared patients with skin lesions with patients without skin lesions and found that provider delay and total time to diagnosis were significantly longer for those with skin lesions than without skin lesions (data not shown).

Time to diagnosis was also significantly shorter for patients who died than for those who survived. Both patient interval and provider interval were shorter for patients who died, probably because their blastomycosis was more severe from the onset, which may have resulted in earlier presentation to health-care and more aggressive initial diagnostics. How-ever, patients who died were not tested for a me-dian of 11 days after their first healthcare visit, and

perhaps some might not have died had a diagnosis been reached sooner.

We anticipated that time to diagnosis would be shorter for patients residing in highly blasto-mycosis-endemic counties because local provid-ers would be more familiar with the disease and would order testing earlier. Although the median time to diagnosis was the same in highly and less disease-endemic counties, patients living in highly disease-endemic counties were 50% less likely to be hospitalized. This finding may indicate that where providers were more familiar with blastomycosis, they more frequently ordered testing before hospi-talization was required.

Although incidence by county of residence provides a measure of disease frequency, 29% of patients were probably exposed outside their home county. Mapping of case totals for county of exposure compared with county of residence illustrates that many patients live in more popu-lated, less blastomycosis-endemic counties, such as Hennepin and Ramsey (i.e., the Minneapolis–St. Paul metropolitan area) but are exposed in highly blastomycosis-endemic northern counties (e.g., Cass, Itasca). By tracking suspected exposure loca-tions, we can more accurately distinguish highly


Figure 4. Treatment delay for blastomycosis patients, by category of case, Minnesota, USA, 1999–2018. A) Patient interval (time of illness onset to first healthcare visit); B) provider interval (time of first visit to first blastomycosis test); and C) total time to diagnosis (time of illness onset to first test). Median (diamonds) and interquartile ranges (error bars) are shown. p values were calculated by using the Kruskal-Wallis and Wilcoxon rank tests and are indicated when significantly different from others in category. *p<0.001; †3rd quartile = 150; p = 0.009; ‡p = 0.001.


blastomycosis-endemic areas. Further refinement of such areas and future exposure location data will provide more information about the ecologic niche of blastomycosis and help focus awareness cam-paigns among healthcare providers, residents, and visitors. Many of the highly blastomycosis-endemic counties attract seasonal residents and tourists in

summer, underscoring the value of travel histories for patients with infectious disease and provider fa-miliarity with geographic areas where risk for Blas-tomyces exposure is greater.

As previously reported, blastomycosis cases were skewed heavily by patient sex. This finding is often attributed to a perceived higher likelihood of


Figure 5. Blastomycosis cases, by county of residence (A; n = 670) and probable county of exposure (B; n = 463), Minnesota, USA, 1999–2018.

Table 2. Exposures and associations of interviewed blastomycosis patients, by sex, Minnesota, USA, 1999–2018*

Exposures and associations All cases, no. (%),

n = 541 Male patients,

no. (%), n = 383 Female patients, no. (%), n = 158 OR (95% CI)† p value†

Outdoor activity 317 (59) 245 (64) 72 (46) 2.1 (1.5–3.1), p<0.001 Hunting 84 (15) 80 (21) 4 (2) 10.5 (3.8–29.2) p<0.001‡ Fishing 161 (30) 134 (35) 27 (17) 2.7 (1.7–4.3) p<0.001 Boating 99 (40) 78 (44) 21 (30) 1.8 (1.0–3.2) p = 0.049 Swimming 59 (27) 47 (29) 12 (21) NS Camping 87 (16) 66 (17) 21 (13) NS Hiking 152 (28) 111 (29) 41 (26) NS Specific soil exposure 375 (78) 276 (80) 99 (72) 1.6 (1.0–2.5) p = 0.050 ATV use 86 (19) 74 (23) 12 (10) 2.8 (1.5–5.4) p = 0.001 Wood clearing/cutting at home 193 (35) 165 (43) 28 (17) 3.6 (2.3–5.7) p<0.001 Garden 148 (34) 101 (34) 47 (36) NS Nearby excavation 172 (32) 124 (33) 48 (30) NS Visiting a cabin 177 (33) 131 (35) 46 (29) NS Nearby beaver dams 86 (16) 67 (18) 19 (12) NS Working in woods§ 97 (21) 88 (26) 9 (7) 4.9 (2.4–10.1) p<0.001 Family member(s) had blastomycosis 22 (4) 11 (3) 11 (7) 0.39 (0.16–0.93) p = 0.029 Owning a dog 283 (53) 197 (52) 86 (54) NS Owning a dog that had blastomycosis 29 (10) 19 (9) 10 (11) NS *Denominators may not be same across categories because not all data were available for all patients. ATV, all-terrain vehicle; OR, odds ratio; NS, not significant. †ORs and p values calculated by using 2 test, except where indicated. ‡p value calculated by using Fisher exact test. §Part-time or full-time employment in wooded areas (e.g., construction, landscaping, forestry).

SYNOPSIS

male patients having engaged in recreational and occupational outdoor activities that increase risk for exposure to Blastomyces (1,5). In Minnesota, 2 other outdoor-associated diseases that occur in similar lo-cations, Lyme disease and anaplasmosis, also occur more often in men, but the male:female ratio (60:40) is less dramatic (29). Male blastomycosis patients reported participation in some outdoor activities at significantly higher proportions than did female patients. However, even when evaluating an expo-sure that should not intuitively differ by sex, such as nearby excavation, 72% of patients were male. Other factors may explain differences by sex, such as hormonal effects, as have been proposed for other diseases (30–32).

A previous retrospective case–control study did not find any association between infection and factors typically associated with blastomycosis in outbreaks, such as proximity to water, recreational activities, or soil-related activities (4). A prospective case–control study would help determine whether those who acquire blastomycosis participate in these exposure activities at higher rates. Most patients in this study reported >1 activity typically considered a risk factor for blastomycosis, but no activities were common to all or most patients. In addition, this study does not enable us to determine which expo-sures present the highest risk because background exposure rates for Minnesota residents are not read-ily available.

Study limitations include those characteristic of surveillance data. Because the surveillance system is passive, undercounting is possible if cases were not reported. Race and ethnicity were not always docu-mented in medical records. Data collection methods changed in 2016 when medical record abstraction was added. Back and bone pain were added to case report forms in 2001; joint pain, boating, and ATV use were added in 2010. Data regarding the number of health-care visits were not consistently available. We used the date of first test for blastomycosis as the endpoint for determining time to diagnosis. However, nega-tive test results are not routinely reported. Although we made every effort to collect this information from medical record abstraction or providers, some could have been missed.

In conclusion, to reduce the time to diagnosis and case-fatality rates for patients with blastomycosis, providers should consider alternative etiologies for patients with pneumonia that is unresponsive to anti-bacterial drugs. Complete travel and exposure histo-ries should be obtained, and antigen testing should be considered as a screening test. Blastomycosis should

be considered an emerging risk for immunocompro-mised or chronically ill patients in disease-endemic regions, even for those who do not report classic exposures. Public health officials should work to in-crease awareness among persons who live and visit blastomycosis-endemic areas so they can advocate for themselves.

AcknowledgmentsWe thank Jeff Bender for creating this blastomycosis surveillance system, Tory Whitten for epidemiologic assistance, Richard Danila and Raj Mody for reviewing the manuscript, and the many MPH students who interviewed patients.

This work was supported in part by a cooperative agreement with the Centers for Disease Control and Prevention as part of the Epidemiology and Laboratory Capacity for Infectious Diseases Program (U50/CK000371).

About the AuthorDr. Ireland is a veterinarian and epidemiologist in the Zoonotic Diseases Unit at the Minnesota Department of Health. Her research interests include endemic fungal diseases and zoonoses transmitted at animal contact venues.

References 1. Saccente M, Woods GL. Clinical and laboratory update on

blastomycosis. Clin Microbiol Rev. 2010;23:367–81. https://doi.org/10.1128/CMR.00056-09

2. Bradsher RW, Chapman SW, Pappas PG. Blastomycosis. Infect Dis Clin North Am. 2003;17:21–40, vii. https://doi.org/10.1016/S0891-5520(02)00038-7

3. Dworkin MS, Duckro AN, Proia L, Semel JD, Huhn G. The epidemiology of blastomycosis in Illinois and factors associated with death. Clin Infect Dis. 2005;41:e107–11. https://doi.org/10.1086/498152

4. Cano MV, Ponce-de-Leon GF, Tippen S, Lindsley MD, Warwick M, Hajjeh RA. Blastomycosis in Missouri: epidemiology and risk factors for endemic disease. Epidemiol Infect. 2003;131:907–14. https://doi.org/10.1017/S0950268803008987

5. Dalcin D, Ahmed SZ. Blastomycosis in northwestern Ontario, 2004 to 2014. Can J Infect Dis Med Microbiol. 2015;26:259–62. https://doi.org/10.1155/2015/468453

6. Litvinov IV, St-Germain G, Pelletier R, Paradis M, Sheppard DC. Endemic human blastomycosis in Quebec, Canada, 1988-2011. Epidemiol Infect. 2013;141:1143–7. https://doi.org/10.1017/S0950268812001860

7. Azar MM, Assi R, Relich RF, Schmitt BH, Norris S, Wheat LJ, et al. Blastomycosis in Indiana: clinical and epidemiologic patterns of disease gleaned from a multicenter retrospective study. Chest. 2015;148:1276–84. https://doi.org/10.1378/chest.15-0289

8. Meece JK, Anderson JL, Gruszka S, Sloss BL, Sullivan B, Reed KD. Variation in clinical phenotype of human infection



among genetic groups of Blastomyces dermatitidis. J Infect Dis. 2013;207:814–22. https://doi.org/10.1093/infdis/jis756

9. Hage CA, Knox KS, Wheat LJ. Endemic mycoses: overlooked causes of community acquired pneumonia. Respir Med. 2012;106:769–76. https://doi.org/10.1016/j.rmed.2012.02.004

10. Alpern JD, Bahr NC, Vazquez-Benitez G, Boulware DR, Sellman JS, Sarosi GA. Diagnostic delay and antibiotic overuse in acute pulmonary blastomycosis. Open Forum Infect Dis. 2016;3:ofw078. https://doi.org/10.1093/ofid/ofw078

11. Brown EM, McTaggart LR, Dunn D, Pszczolko E, Tsui KG, Morris SK, et al. Epidemiology and geographic distribution of blastomycosis, histoplasmosis, and coccidioidomycosis, Ontario, Canada, 1990–2015. Emerg Infect Dis. 2018;24: 1257–66. https://doi.org/10.3201/eid2407.172063

12. Reed KD, Meece JK, Archer JR, Peterson AT. Ecologic niche modeling of Blastomyces dermatitidis in Wisconsin. PLoS One. 2008;3:e2034. https://doi.org/10.1371/journal.pone.0002034

13. Brown EM, McTaggart LR, Zhang SX, Low DE, Stevens DA, Richardson SE. Phylogenetic analysis reveals a cryptic species Blastomyces gilchristii, sp. nov. within the human pathogenic fungus Blastomyces dermatitidis. PLoS One. 2013;8:e59237. https://doi.org/10.1371/journal.pone.0059237

14. McTaggart LR, Brown EM, Richardson SE. Phylogeographic analysis of Blastomyces dermatitidis and Blastomyces gilchristii reveals an association with North American freshwater drainage basins. PLoS One. 2016;11:e0159396. https://doi.org/10.1371/journal.pone.0159396

15. Schwartz IS, Wiederhold NP, Hanson KE, Patterson TF, Sigler L. Blastomyces helicus, a new dimorphic fungus causing fatal pulmonary and systemic disease in humans and animals in western Canada and United States. Clin Infect Dis. 2019;68:188–95.

16. Lohrenz S, Minion J, Pandey M, Karunakaran K. Blastomycosis in southern Saskatchewan 2000-2015: unique presentations and disease characteristics. Med Mycol. 2018;56:787–95. https://doi.org/10.1093/mmy/myx131

17. Klein BS, Vergeront JM, Weeks RJ, Kumar UN, Mathai G, Varkey B, et al. Isolation of Blastomyces dermatitidis in soil associated with a large outbreak of blastomycosis in Wisconsin. N Engl J Med. 1986;314:529–34. https://doi.org/ 10.1056/NEJM198602273140901

18. Pfister JR, Archer JR, Hersil S, Boers T, Reed KD, Meece JK, et al. Non-rural point source blastomycosis outbreak near a yard waste collection site. Clin Med Res. 2011;9:57–65. https://doi.org/10.3121/cmr.2010.958

19. Roy M, Benedict K, Deak E, Kirby MA, McNiel JT, Sickler CJ, et al. A large community outbreak of blastomycosis in Wisconsin with geographic and ethnic clustering. Clin Infect Dis. 2013;57:655–62. https://doi.org/ 10.1093/cid/cit366

20. Armstrong CW, Jenkins SR, Kaufman L, Kerkering TM, Rouse BS, Miller GB Jr. Common-source outbreak of

blastomycosis in hunters and their dogs. J Infect Dis. 1987;155:568–70. https://doi.org/10.1093/infdis/155.3.568

21. Cockerill FR III, Roberts GD, Rosenblatt JE, Utz JP, Utz DC. Epidemic of pulmonary blastomycosis (Namekagon fever) in Wisconsin canoeists. Chest. 1984;86:688–92. https://doi.org/10.1378/chest.86.5.688

22. Klein BS, Vergeront JM, DiSalvo AF, Kaufman L, Davis JP. Two outbreaks of blastomycosis along rivers in Wisconsin. Isolation of Blastomyces dermatitidis from riverbank soil and evidence of its transmission along waterways. Am Rev Respir Dis. 1987;136:1333–8. https://doi.org/10.1164/ ajrccm/136.6.1333

23. Khuu D, Shafir S, Bristow B, Sorvillo F. Blastomycosis mortality rates, United States, 1990–2010. Emerg Infect Dis. 2014;20:1789–94. https://doi.org/10.3201/eid2011.131175

24. Frost HM, Anderson J, Ivacic L, Meece J. Blastomycosis in children: an analysis of clinical, epidemiologic, and genetic features. J Pediatric Infect Dis Soc. 2017;6:49–56. https://doi.org/10.1093/jpids/piv081

25. National Center for Health Statistics. US Census populations with bridged race categories [cited 2018 Jul 6]. https://www.cdc.gov/nchs/nvss/bridged_race.htm

26. Merkhofer RM Jr, O’Neill MB, Xiong D, Hernandez-Santos N, Dobson H, Fites JS, et al. Investigation of genetic susceptibility to blastomycosis reveals interleukin-6 as a potential susceptibility locus. MBio. 2019;10:e01224-19. https://doi.org/10.1128/mBio.01224-19

27. Castillo CG, Kauffman CA, Miceli MH. Blastomycosis. Infect Dis Clin North Am. 2016;30:247–64. https://doi.org/ 10.1016/j.idc.2015.10.002

28. Lemos LB, Baliga M, Guo M. Blastomycosis: the great pretender can also be an opportunist. Initial clinical diagnosis and underlying diseases in 123 patients. Ann Diagn Pathol. 2002;6:194–203. https://doi.org/10.1053/adpa.2002.34575

29. Minnesota Department of Health. Lyme disease [cited 2019 Jul 2]. https://data.web.health.state.mn.us/web/mndata/lyme_facts

30. Guess TE, Rosen JA, McClelland EE. An overview of sex bias in C. neoformans infections. J Fungi (Basel). 2018;4:E49. https://doi.org/10.3390/jof4020049

31. Shankar J, Restrepo A, Clemons KV, Stevens DA. Hormones and the resistance of women to paracoccidioidomycosis. Clin Microbiol Rev. 2011;24:296–313. https://doi.org/10.1128/CMR.00062-10

32. Bernin H, Lotter H. Sex bias in the outcome of human tropical infectious diseases: influence of steroid hormones. J Infect Dis. 2014;209(Suppl 3):S107–13. https://doi.org/ 10.1093/infdis/jit610

Address for correspondence: Malia Ireland, Minnesota Department of Health, 625 Robert St N, St. Paul, MN 55164, USA; email: [email protected]


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SYNOPSIS Blastomycosis in Minnesota, USA, 1999–2018 · Risk factors for sporadic cases are less...

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